The passive permeability of skeletal muscle sarcoplasmic reticulum vesicles to Ca2+ ions is drastically increased upon addition of the oxidizing agent cupric phenanthroline. The permeability change, which occurs very rapidly, is partially reversed by reducing agents and cannot be explained by a direct effect of cupric phenanthroline on the lipid moiety of the membranes. The rapid efflux phenomenon is due to protein cross-linking induced by the cupric phenanthroline catalyzed oxidation of SH groups to disulfide bridges. Similar effects are also induced by cross-linking sarcoplasmic reticulum proteins with dithiodipropionic acid disuccinimido ester. The rapid Ca2+ efflux is inhibited by micromolar concentrations of lanthanum and by labeling the Ca2+-ATPase with dicyclohexylcarbodiimide. These observations suggest that Ca2+ channels are formed by chemical modification of the ATPase. The Ca2+ permeability rate of sarcoplasmic reticulum obtained after cross-linking is compatible with the requirements of Ca2+ release in vivo. The possibility that Ca2+-ATPase oligomers might mediate the release process is discussed.